Myocardial dysfunction and resulting low cardiac output syndrome (LCOS) contribute significantly to postoperative morbidity and mortality in pediatric heart surgery. Despite major advances in diagnostic accuracy and intra-operative myocardial protection strategies, LCOS remains an important clinical problem with an estimated incidence of ~25% in infants undergoing cardiopulmonary bypass. This application proposes a multi-center, randomized, double blind, placebo-controlled clinical trial, to investigate whether preoperative administration of glucocorticoids (methylprednisolone, steroids) and/or erythropoietin (EPO) will afford protection from ischemia-reperfusion injury and thereby reduce the incidence of LCOS for infants undergoing cardiopulmonary bypass. Furthermore, although there are important interactions between these two agents, the primary signaling pathways are distinct;hence, combined use may result in a synergistic reduction in the incidence of LCOS. There will be four preoperative treatment arms: 1) placebo;2) steroids;3) EPO;and 4) steroids and EPO combined. The study design assumes that intra-operative steroids will be administered. This assumption is based on a recent published survey documenting this as common practice in pediatric centers, and our own investigations that demonstrate an improved benefit from pre- and intraoperative steroid use. The Primary Aim of the proposed study is to compare the effect of preoperative steroids and/or EPO with placebo on LCOS incidence through the first 48 hours following cardiopulmonary bypass surgery. Hypotheses to be tested include: 1) Preoperative steroids protect against ischemia-reperfusion injury to enhance myocardial performance postoperatively, resulting in a lower incidence of LCOS. 2) Preoperative EPO protects cardiomyocytes during ischemia-reperfusion, resulting in improved myocardial performance postoperatively with a subsequent reduction in the incidence of LCOS. 3) Concurrent administration of preoperative steroids and EPO will have a synergistic effect to reduce the incidence of LCOS. The Primary Outcome is LCOS. The diagnosis of LCOS will be based on a composite of clinical signs and symptoms, biochemical markers, and the need for additional inotropic/mechanical support. Five Secondary Aims will assess treatment effects on mortality and clinical measures of morbidity, postoperative myocardial performance, inflammatory and non-inflammatory mediators of myocardial dysfunction pre- and post-heart surgery, cardiomyocyte protection and apoptosis pre- and post-cardiopulmonary bypass surgery and the incidence of renal injury within 48 hours after cardiopulmonary bypass surgery. Completion of the proposed studies should greatly improve our understanding of ischemia-reperfusion injury and therapies to prevent LCOS following surgery with cardiopulmonary bypass in infants. (End of Abstract)